Estra-3-keto-4,9(10)-diene steroids (all steroids herein have the natural stereochemistry unless otherwise defined), the products of this invention, are known valuable intermediates to biologically active substances (see G. Teutsch in Adrenal Steroid Antagonism, 5d. M. K. Agarwal, W. deGruyter and G. Berlin, 1984, pp. 43-75). U.S. Pat. No. 3,461,118 prepares this 3-keto-4,9(10)-diene structural feature from a 3-keto-xcex945(10)-steroid by a process using bromine and pyridine. In the patent, the 3-keto-xcex945(10)-steroid is produced by hydrolysis of the corresponding ketal, but it also can be made by many chemical routes (see CAN 69:77598; NL 6608779), most prominent among them by a Birch reduction of the 3-protected estrone followed by hydrolysis (see CAN 66:65723, NL 6607002).
In French Patent 1,568,711, this same 3-keto starting material, estra-5(10)-ene-3-one steroid, is converted into the subject estra-3-keto-4,9(10)-diene steroids, by a chlorination or iodination process as well as a process of epoxidation, epoxide opening under strongly basic conditions (i.e. potassium hydroxide in refluxing methanol), to produce the 10-hydroxy-estra-4-ene-3,17-dione which is an intermediate of the present invention. This intermediate is carried on by methane sulfonate ester formation followed by treatment with sodium acetate in acetic acid, a process very different from the present invention, and using a starting material different from the present invention.
The following Chart A illustrates the process of the invention, including the steroid structures and functional group variations. Chart B illustrates steroid structures related to those shown in Chart A.
Disclosed are steroidal epoxides (II) of estra-5(10)-ene-3,17-dione-3,17-bis-ketals (I), specifically 7xcex1-methyl-5(10)-oxido-estra-3,17-dione steroids (IIA), 10-hydroxy-estra-4-ene-3-one steroids (III), and 5,10-dihydroxy-estra-3-one steroids (IV). Also disclosed is a process for preparation of a steroid having the 4,9(10)-diene-3-one structure (VA) by contacting a 10-hydroxy-4-ene-3-ketosteroid (IIIA) and/or a 5,10-dihydroxy-3-ketosteroid (IVA) with concentrated sulfuric acid or moderated sulfuric acid. Further disclosed is a process for preparing estra-3-keto-4,9(10)-diene steroids (V) starting with estra-5(10)-ene-3,17-dione-3,17-bis-ketals (I), derivable from 19-nor-androst-4-ene-3-one steroids, comprising contacting (a) xcex945(10)-bis-ketals (I) with an epoxidizing agent to prepare epoxides (II), (b) contacting the epoxides (II) with dilute acid to produce hydroxy compounds (III) and (IV), and (c) contacting the hydroxy compounds (III) and (IV) with concentrated sulfuric acid. Also disclosed is a process for preparation of steroidal estra-4,9(10)-diene-3,17-diones of structure (V) by treatment of steroidal estra-5(10),9(11)-diene-3,17-diones of structure (VI) with concentrated mineral acid. 
The estra-5(10)-ene-3,17-dione-3,17-bis-ketals (I), the starting materials for the process of the invention, are known in the art: for examples see John F. Templeton et al., J. Chem. Soc., Perkin Trans. 1 (1994), (9), 1149-58; and C. Djerassi, et al., J. Am. Chem. Soc., vol. 81, p 3120 (1959). As shown in Chart A, these xcex945(10)-bis-ketals (I) are typically derived from the readily available 19-nor-androst-4-ene-3-one steroids by standard ketalization methods. Of the many ketals possible, it is preferred that the ketal be derived from ethylene glycol or neopentyl glycol, the latter most preferred.
The structure and functional group variations of the xcex945(10)-bis-ketals (I) are shown in the chart. Some nonlimiting examples of preferred xcex945(10)-bis-ketals (I) for use in the invention include 7xcex1-methyl-estra-5(10)-ene-3,17-dione-3,17-bis-ethylene glycol ketal, 7xcex1-methyl-estra-5(10)-ene-3,17-dione-3,17-bis-neopentyl glycol ketal, and estra-5(10)-ene-3,17-dione-3,17-bis-neopentyl glycol ketal.
As shown in Chart A, the estra-5(10)-ene-3,17-dione-3,17-bis-ketals (I) are epoxidized to produce bis ketal-5(10)-epoxide products (II). Epoxidation of olefins is a standard reaction in organic chemistry (see Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1-20, John Wiley and Sons, Inc., N.Y. 1967-2000), but epoxidation of the olefin in xcex945(10)-bis-ketals (I) has not been reported, nor have the requisite epoxide products (II) been reported. Many epoxidizing agents may be used, but preferred is the use of m-chloroperbenzoic acid or peracetic acid in solvents that do not react with peracids, such as methylene chloride. The epoxidizing reaction can be conducted under a wide range of temperatures, but preferred is 0xc2x0 C. to ambient. The bis-ketal-5(10)-epoxide products (II) are isolated in high conversion by a standard workup, and generally need no further purification by crystallization or chromatography.
The structure and functional group variations of the bis-ketal-5(10)-epoxides (II) are shown in the chart. In some preferred embodiments of the structure, X=C(CH3)2 and R1=CH3, R2=R3=H. Some nonlimiting examples of preferred bis-ketal-5(10)-epoxides (II) for use in the invention include 7xcex1-methyl-5(10)-oxido-estra-3,17-dione-3,17-bis-ethylene glycol ketal, 7xcex1-methyl-5(10)-oxido-estra-3,17-dione-3,17-bis-neopentyl glycol ketal, and 5(10)-oxido-estra-3,17-dione-3,17-bis-neopentyl glycol ketal.
As shown in Chart B, 7xcex1-methyl-5(10)-oxido-estra-3,17-dione steroids (IIA) is the product from epoxidation of the xcex945(10)-bis-ketals (I) (R1=Ch3, R2=R3=H) to the bis-ketal-5(10)-epoxide products (II) (R1=Ch3, R2=R3=H) followed by mild acid hydrolysis.
Referring again to Chart A, in a second step of the process, the bis-ketal-5(10)-epoxides (II) are contacted under dilute acidic conditions to effect both ketal hydrolysis and epoxide opening to give mixtures of 10-hydroxy-estra-4-ene-3-ones (III) and 5,10-dihydroxy-estra-3-ones (IV). The ratio of these monohydroxy and dihydroxy products is not important for the purposes of this invention because both are efficiently converted into the estra-4,9(10)-diene-3-ones (V), the end product of this invention. Many acids and many solvents with water may be used to effect conversion of (II) to (III) and (IV), but preferred are dilute aqueous mineral acids in water miscible solvents such as acetone or tetrahydrofuran. More preferred is contact of the epoxy ketals (II) with xcx9c0.5 M hydrochloric acid in acetone at ambient temperature. The reaction products (III) and (IV) may be isolated by extractive procedures or preferably as a solid by evaporation of the volatile solvent.
The structures and functional group variations of the reaction products (III) and (IV) are shown in the chart. In some preferred embodiments of compounds (III), R1=CH3, R2=R3=H; or R1=R2=R3=H. Some nonlimiting examples of preferred 10-hydroxy-estra-4-ene-3-ones (III) for use in the invention include 10-hydroxy-7xcex1-methyl-estra-4-ene-3,17-dione, 10-hydroxy-6xcex1-methyl-estra-4-ene-3,17-dione, and 10-hydroxy-estra-4-ene-3,17-dione. In some preferred embodiments of compounds (IV), R1=CH3, R2=R3=H; or R1=R2=R3=H. Some nonlimiting examples of preferred 5,10-dihydroxy-estra-3-ones (IV) for use in the invention include 5,10-dihydroxy-7xcex1-methyl-estra-3,17-dione, 5,10-dihydroxy-6xcex1-methyl-estra-3,17-dione, and 5,10-dihydroxy-estra-3,17-dione.
In the final step of the process (Chart A), the 10-hydroxy-estra-4-ene-3-ones (III) and 5,10-dihydroxy-estra-3-ones (IV) are converted by acidic dehydration to the product of this invention, estra-3-keto-4,9(10)-diene steroids (V). This conversion is surprisingly and unexpectedly specific to concentrated sulfuric acid and slightly moderated forms of sulfuric acid. Other readily available concentrated acids do not efficiently make this conversion. Those acids which give none or poor conversions to the target estra-3-keto-4,9(10)-diene steroids (V) of this invention include phosphoric acid, formic acid, trifluoroacetic acid, acetic acid, and methanesulfonic acid.
By xe2x80x9cconcentratedxe2x80x9d sulfuric acid is meant sulfuric acid at a concentration of at least 95%, and typically 95-99%. The sulfuric acid can be moderated by admixture with water, with the water being present in an amount of up to 5% by volume of the moderated acid. The sulfuric acid can also be moderated by admixture with a second acid, such as one of the abovementioned acids, or mixtures of different acids. The second acid is present in an amount of up to 30% by volume of the moderated acid. Preferred is concentrated phosphoric acid (concentration of at least 85%), preferably at a ratio of about ⅙ of volume of sulfuric acid. The speed and reactivity of the reaction can be adjusted to the requirements of individual substrates by adjusting this ratio, the greater reactivity with the lowest amount of phosphoric acid. It is convenient to dissolve the hydroxy compounds (III) and (IV) in an inert solvent such as methylene chloride before adding them to the concentrated or moderated sulfuric acid. The hydroxy compounds may also be added directly as a solid to the concentrated or moderated sulfuric acid. The preferred reaction temperature is ambient to 0xc2x0 C., although other temperatures may be used. The estra-3-keto-4,9(10)-diene steroid product (V) is conveniently isolated from the sulfuric acid reaction by adding ice, partial neutralization, extraction with acid stable, water immiscible solvent (preferably methylene chloride), evaporation and crystallization.
The structure and functional group variations of the estra-3-keto-4,9(10)-diene steroids (V) are shown in the chart. Some nonlimiting examples of preferred products (V) of the invention include 7xcex1-methyl-estra-4,9(10)-diene-3,17-dione, 6xcex1-methyl-estra-4,9(10)-diene-3,17-dione, 16xcex2-methyl-estra-4,9(10)-diene-3,17-dione, and estra-4,9(10)-diene-3,17-dione. In one embodiment of the overall process of the invention, 7xcex1-methyl-estra-4,9(10)-diene-3,17-dione (V) is prepared from 7xcex1-methyl-estra-5(10)-ene-3,17-dione-3,17-bis-ethylene glycol ketal (I) or 7xcex1-methyl-estra-5(10)-ene-3,17-dione-3,17-bis-neopentyl glycolketal (I). In another embodiment, estra-4,9(10)-diene-3,17-dione (V) is prepared from estra-5(10)-ene-3,17-dione-3,17-bis-ethylene glycol ketal (I) or estra-5(10)-ene-3,17-dione-3,17-bis-neopentyl glycolketal (I).
More generally, the acidic dehydration process described above is useful for converting 10-hydroxy-4-ene-3-ketosteroids (IIIA), 5,10-dihydroxy-3-ketosteroids (IVA), and mixtures of (IIIA) and (IVA), into steroids having the 4,9(10)-diene-3-one structure (VA) (all shown in Chart B). In one preferred embodiment of the process, estra-4,9(10)-diene-3,17-dione (VA) is prepared from 10-hydroxy-estra-4-ene-3,17-dione (IIIA), 5,10-dihydroxy-estra-3,17-dione (IVA), or mixtures thereof. In another embodiment of the process, 7xcex1-methyl-estra-4,9(10)-diene-3,17-dione (VA) is prepared from 10-hydroxy-7xcex1-methyl-estra-4-ene-3,17-dione (IIIA), 5,10-dihydroxy-estra-3,17-dione (IVA), or mixtures thereof.
As further shown in Chart A, dienes of structure (VI) are intermediates and by-products from reaction of (III) and/or (IV) with sulfuric acid and moderated sulfuric acid. Dienes of structure (VI) (R1=R2=R3=H or R1=CH3, R2=R3=H) are known in the literature: see U.S. Pat. No. 3,691,215 and M. Rosenberger et al., J. Org. Chem. 43, 1550 (1978) for conversion of (VI) into (V). In another embodiment of the present invention, concentrated mineral acid (at least 85% concentration) is used to effectively produce the product, estra-3-keto-4,9(10)-diene steroids (V), by contact with the estra-3-keto-5(10),9(11)-diene steroids of structure (VI). Any suitable concentrated mineral acid or mixtures thereof can be used, such as phosphoric and/or sulfuric acid. Mineral acid high in phosphoric acid is preferred, and most preferred is concentrated phosphoric acid.